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The American Journal of Clinical Nutrition logoLink to The American Journal of Clinical Nutrition
. 2012 Mar 21;95(5):1055–1059. doi: 10.3945/ajcn.111.032060

Relations between obesity, insulin resistance, and 25-hydroxyvitamin D123

Cynthia A Lamendola, Danit Ariel, David Feldman, Gerald M Reaven
PMCID: PMC3325832  PMID: 22440850

Abstract

Background: Although low circulating 25-hydroxyvitamin D [25(OH)D] concentrations have been associated with insulin resistance and obesity, the relations between these 3 variables have not been completely resolved.

Objective: The objective was to compare circulating 25(OH)D concentrations in apparently healthy individuals who were matched for degree of obesity or insulin sensitivity.

Design: This was a case-control study in which 78 apparently healthy individuals were classified as being normal weight (NW) or obese (OB) on the basis of their BMI and as being insulin sensitive (IS) or insulin resistant (IR) on the basis of their steady state plasma glucose (SSPG) concentration during the insulin suppression test.

Results: Groups did not differ in terms of age, sex distribution, race, or mean (±SD) plasma 25(OH)D concentration. Values for 25(OH)D were 32 ± 10, 30 ± 10, and 28 ± 8 ng/mL in NW-IS, OB-IS, and OB-IR groups, respectively. These concentrations were essentially identical when comparing IR with IS subjects matched for BMI or when comparing OB with NW subjects matched for SSPG. Concentrations of 25(OH)D ≤30 ng/mL were somewhat more common in OB subjects than in NW subjects (54% compared with 35%), but SSPG concentrations were not different within either the IR or IS groups when subgroups with 25(OH)D concentrations ≤30 or >30 ng/mL were compared.

Conclusions: In 78 individuals, 47% of whom were vitamin D deficient or insufficient (≤30 ng/mL), 25(OH)D concentrations did not vary with differences in insulin sensitivity (SSPG concentration) when matched for BMI (OB-IR compared with OB-IS). Similarly, when matched for SSPG concentrations, plasma 25(OH)D concentrations were not different in NW or OB individuals (NW-IS compared with OB-IS).

INTRODUCTION

Vitamin D deficiency is frequently found in the population at large and is considered to be a potential contributor to the development of several chronic diseases, including type 2 diabetes (T2D)4 (1–3). Obesity is a risk factor for T2D (4) and is associated with vitamin D deficiency (5). Insulin resistance is likely the link between obesity and risk of T2D (6, 7), and T2D develops when insulin-resistant individuals no longer secrete the amount of insulin needed to overcome the defect in insulin action (7). Thus, the conclusion by Chiu et al (8) that low concentrations of 25-hydroxyvitamin D [25(OH)D] were associated with decreased insulin sensitivity and insulin secretory function was of interest. Subsequently, Kayaniyil et al (9), using surrogate estimates of insulin sensitivity and secretion, reported similar results; and additional studies (10–12) have reported an inverse relation between 25(OH)D concentration and insulin sensitivity. However, a clinical trial (13) of cholecalciferol administration to patients with “glucose intolerance or early diabetes” resulted in improvement in insulin secretory response to intravenous glucose, without any change in insulin sensitivity. The role of vitamin D in modulation of insulin action, insulin secretion, or both is further confounded by evidence that the relation between 25(OH)D concentrations and estimates of insulin secretion or action disappears when adjusted for differences in degree of adiposity (14–17).

There are multiple possible explanations for the lack of unanimity concerning the relations between obesity, insulin action and secretion, and plasma 25(OH)D concentrations, but 3 factors seem to stand out. First, almost all studies since the report of Chiu et al (1) have used surrogate estimates of insulin action and not specific quantitative measurements of insulin-mediated glucose disposal. Second, most studies have evaluated these relations in large populations, relying on statistical methods to “adjust” for possible confounding covariates. Third, it is unclear whether low concentrations of 25(OH)D are simply secondary to increased amounts of adiposity or important contributors to abnormal insulin action, insulin secretion, or both.

We have addressed these potential drawbacks by directly measuring insulin-mediated glucose disposal in apparently healthy subjects by using these data to stratify subjects into insulin-resistant (IR) and insulin-sensitive (IS) groups. In addition, the 2 subgroups were matched for degree of adiposity. This approach differentiates our study from most previous publications in 2 regards: 1) the use of a specific method to quantify insulin action and 2) the direct comparison of 25(OH)D concentrations in groups matched for obesity, differing in insulin action, and in groups matched for insulin action, differing in degree of obesity.

SUBJECTS AND METHODS

The experimental findings are based on analysis of stored plasma specimens of 78 subjects, both women and men, who had responded to newspaper advertisements describing our studies of the role of insulin resistance in human disease between 2003 and 2008. Volunteers had a normal medical history, physical examination, and laboratory values and did not have a history of using vitamin D supplements. Stanford University's Human Subjects Committee approved the study protocol, and subjects gave written informed consent. Volunteers were initially divided into normal-weight [NW; BMI (in kg/m2) <25] or obese (OB; BMI ≥30.0 and <35.0) subgroups, and further divided into IS or IR subgroups by the insulin suppression test as described below.

The ability of insulin to dispose of a continuous intravenous glucose infusion was quantified by a modified version (18) of the insulin suppression test as introduced and validated by our research group (19, 20). After an overnight fast, an intravenous catheter was placed in one arm for a 180-min infusion of octreotide (0.27 μg ⋅ m−2 ⋅ min−1), insulin (32 mU ⋅ m−2 ⋅ min−1), and glucose (267 mg ⋅ m−2 ⋅ min−1) and in another arm to obtain blood for measurement of plasma glucose and insulin concentrations 150, 160, 170, and 180 min after starting the infusion. These values were averaged to obtain the steady state plasma glucose (SSPG) and steady state plasma insulin (SSPI) concentrations for each individual. Because octreotide suppresses endogenous insulin secretion, SSPI concentrations are similar, both qualitatively and quantitatively, in all individuals. Consequently, the height of the SSPG concentration provides a direct measure of how effective the insulin was in mediating disposal of the infused glucose load; the higher the SSPG concentration, the less effective the insulin, and the more insulin resistant the individual. Estimates of insulin action determined with the insulin suppression test are highly correlated (R > 0.9) with those obtained by using the hyperinsulinemic euglycemic clamp method (20). On the basis of results of prospective outcome studies (21, 22), insulin resistance was defined as an SSPG concentration ≥180 mg/dL, and insulin sensitivity was defined as an SSPG concentration ≤100 mg/dL.

Values for BMI and SSPG concentrations were used to divide subjects into 3 experimental groups, designated as NW-IS, OB-IS, or OB-IR, for comparison of their plasma 25(OH)D concentrations. Waist circumference (WC) was also determined but not used to classify subjects. Plasma 25(OH)D concentrations were measured at Heartland Assays (Ames, IA) by using a radioimmunoassay that measures D2 and D3, as described by Hollis et al (23). On the basis of these values, subjects were also classified as being vitamin D deficient [25(OH)D concentrations <20 ng/mL] or vitamin D insufficient [25(OH)D concentrations of 20–30 ng/mL] by using criteria outlined in the 2011 Clinical Practice Guidelines of the Endocrine Society (24). Statistical analysis was performed by using the R Commander package of the statistical software R version 2.2.1 (The R Foundation for Statistical Computing). Normality of distribution was assessed with a histogram of the data as compared with a normal probability curve as well as with a quantile-quantile plot as a visual graphical tool. Baseline characteristics were compared with the use of a 1-factor ANOVA, chi-square test, or Fisher's exact test. Data are presented as means ± SDs unless otherwise specified. Significance was defined as P < 0.05.

RESULTS

Some relevant characteristics of the 3 experimental groups are presented in Table 1. Two IS groups (NW and OB) differed substantially in their values for BMI and WC. However, the SSPG concentrations of the 2 groups were comparable, as were their fasting plasma glucose and fasting plasma insulin concentrations. Most notably, they had almost identical 25(OH)D concentrations even with substantial differences in adiposity. It should be emphasized that there was no overlap in BMI and WC values of the NW-IS and OB-IS groups. The SSPI concentrations were lower, on average, in the OB-IS group, and this may have led to an underestimation of their relative degree of insulin sensitivity.

TABLE 1.

Demographic and metabolic characteristics of the experimental groups1

Variable NW-IS(n = 26) OB-IS(n = 26) OB-IR (n = 26) P value
Age (y) 52 ± 82 54 ± 7 50 ± 8 0.19
Sex (% male) 50 46 46 0.95
Race (% white) 89 85 85 1.0
BMI (kg/m2) 22.5 ± 1.5 32.0 ± 1.2 32.1 ± 1.3 <0.001
WC (cm) 84 ± 9 106 ± 9 104 ± 8 <0.001
FPG (mg/dL) 92 ± 6 94 ± 9 100 ± 11 <0.001
FPI (μU/mL) 9 ± 7 12 ± 6 23 ± 10 <0.001
SSPG (mg/dL) 70 ± 12 75 ± 14 221 ± 32 <0.001
SSPI (μU/mL) 86 ± 7 67 ± 11 87 ± 20 0.10
25(OH)D (ng/mL) 32 ± 10 30 ± 10 28 ± 8 0.25
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1

P values were calculated by using 1-factor ANOVA, Fisher's exact test, and chi-square test. Significance was set at P < 0.05 for all comparisons. FPG, fasting plasma glucose; FPI, fasting plasma insulin; NW-IS, normal weight and insulin sensitive; OB-IR, obese and insulin resistant; OB-IS, obese and insulin sensitive; SSPG, steady state plasma glucose; SSPI, steady state plasma insulin; WC, waist circumference; 25(OH)D, 25-hydroxyvitamin D.

2

Mean ± SD (all such values).

In the case of the 2 OB groups (OB-IS and OB-IR), BMI and WC values were not different. However, despite a similar degree of adiposity, SSPG, fasting plasma insulin, and fasting plasma glucose concentrations were higher in the OB-IR group. This striking evidence of insulin resistance in the OB-IR group was associated with 25(OH)D concentrations that were no different from those in OB-IS individuals. The somewhat higher SSPI concentration in the OB-IR group may have minimized to some degree the magnitude of the differences in SSPG concentrations in the 2 OB groups.

Plasma 25(OH)D concentrations in the 3 experimental groups are compared in Figure 1 and were comparable, irrespective of differences in obesity and insulin sensitivity. It should be noted that this seems to be the case in terms of both mean concentrations and the ranges of values. Thus, in IS subjects, 25(OH)D concentrations did not vary as a function of being either normal weight (NW-IS) or obese (OB-IS). Similarly, in the case of OB individuals, 25(OH)D concentrations were not different, despite 3-fold differences in SSPG concentrations in OB-IS compared with OB-IR subjects.

FIGURE 1.

FIGURE 1.

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Comparison of mean and individual 25-hydroxyvitamin D concentrations in the 3 experimental groups. There were 26 individuals in each of the 3 groups. There were no significant differences between the groups as assessed by 1-factor ANOVA. NW-IS, normal weight and insulin sensitive; OB-IR, obese and insulin resistant; OB-IS, obese and insulin sensitive.

The results presented to this point included individuals whose 25(OH)D concentrations ranged from deficient to insufficient to sufficient using the 2011 Clinical Practice Guidelines of the Endocrine Society (24): 13 subjects (17%) were vitamin D deficient and 24 (31%) were vitamin D insufficient.

As shown in Table 2, a comparison was made of relevant experimental variables in the 3 experimental groups, using a 25(OH)D concentration cutoff of 30 ng/mL (24) to divide them into vitamin D–sufficient (>30 ng/mL) and vitamin D–deficient/insufficient (≤30 ng/mL) subgroups. The 2 obese groups contained a somewhat greater proportion of individuals whose 25(OH)D concentrations were ≤30 ng/mL (OB-IS, n = 12; OB-IR, n = 16; 28/52 = 54%) as compared with NW subjects (9/26 = 35%), but this difference was not significant. The 25(OH)D concentrations, as expected, were significantly lower (P < 0.001) in the vitamin D–deficient/insufficient subgroup as compared with the vitamin D–sufficient subgroup in the NW-IS, OB-IS, and OB-IR experimental groups. However, despite this ∼2-fold difference in 25(OH)D concentration, there were no differences in the values for age, BMI, WC, and SSPG concentration when comparing the vitamin D–sufficient with the vitamin D–deficient/insufficient subgroups within any of the 3 basic experimental groups. Because only 17% (13/78) of subjects had 25(OH)D concentrations ≤20 ng/mL, we could not perform a similar detailed analysis. However, when we used this cutoff to compare subjects who were above and below the cutoff in the NW-IS, OB-IS, and OB-IR groups, the results were similar to those shown in Table 2—ie, there were significant differences in 25(OH)D concentrations but essentially identical SSPG concentrations.

TABLE 2.

Comparison of variables in subgroups with 25(OH)D concentrations ≤30 or >30 ng/mL1

NW-IS
 OB-IS
 OB-IR
Variables ≤30 ng/mL(n = 9) >30 ng/mL(n = 17) P ≤30 ng/mL(n = 12) >30 ng/mL(n = 14) P ≤30 ng/mL(n = 16) >30 ng/mL(n = 10) P
Age (y) 52 ± 62 51 ± 9 0.77 54 ± 6.5 54 ± 6.7 0.99 50 ± 8 50 ± 8 0.92
Sex (M/F) 5/4 8/9 1.0 5/7 7/7 0.67 7/9 5/5 1.0
Race (% white) 78 94 0.42 83 86 0.85 81 90 0.76
BMI (kg/m2) 22.4 ± 1.3 22.5 ± 1.6 0.77 32.3 ± 1.3 31.7 ± 1.0 0.20 31.8 ± 1.2 32.5 ± 1.5 0.24
WC (cm) 82 ± 8 85 ± 9 0.47 108 ± 9 104 ± 9 0.36 103 ± 80 106 ± 9 0.40
SSPG (mg/dL) 73 ± 13 68 ± 12 0.32 77 ± 12 72 ± 15 0.36 217 ± 32 229 ± 32 0.34
25(OH)D (ng/mL) 22 ± 6 37 ± 7 <0.001 21 ± 5 37 ± 6 <0.001 23 ± 6 35 ± 5 <0.001
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1

P values were calculated by using 1-factor ANOVA, Fisher's exact test, and chi-square test. By using 2-factor ANOVA, we found no significant interaction between group and 25(OH)D category. Significance was set at P < 0.05 for all comparisons. NW-IS, normal weight and insulin sensitive; OB-IR, obese and insulin resistant; OB-IS, obese and insulin sensitive; SSPG, steady state plasma glucose; WC, waist circumference; 25(OH)D, 25-hydroxyvitamin D.

2

Mean ± SD (all such values).

Although dichotomous cutoffs for BMI and SSPG concentrations were used to create the NW-IS, OB-IS, and OB-IR groups, 25(OH)D concentrations varied. Thus, to further analyze the relations of interest, subjects were divided into tertiles on the basis of their 25(OH)D concentrations (Table 3).

TABLE 3.

Comparison of variables in tertiles of 25(OH)D concentration1

Variable Tertile 1(n = 26) Tertile 2(n = 26) Tertile 3(n = 26) P value
25(OH)D (ng/mL)2 9.1–25.8 25.9–32.3 33.1–58.0 NA
Age (y) 52 ± 83 52 ± 8 52 ± 7 0.95
Sex (% male) 54 35 54 0.28
Race (% white) 77 92 88 0.15
BMI (kg/m2) 30.1 ± 4.2 28.8 ± 4.2 27.7 ± 5.5 0.18
WC (cm) 101 ± 13 96 ± 11 97 ± 16 0.43
SSPG (mg/dL) 141 ± 76 119 ± 70 106 ± 74 0.21
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1

P values were calculated by using 1-factor ANOVA, Fisher's exact test, and chi-square test. Significance was set at P < 0.05 for all comparisons. NA, not applicable; SSPG, steady state plasma glucose; WC, waist circumference; 25(OH)D, 25-hydroxyvitamin D.

2

Values are ranges.

3

Mean ± SD (all such values).

Subjects in the lowest 25(OH)D tertile were less likely to be white and had somewhat higher values for BMI and SSPG concentrations, but none of these differences were significant.

DISCUSSION

We believe that the results of this study provide new and useful information concerning the relation between circulating plasma 25(OH)D concentrations, obesity, and insulin resistance. By focusing initially on the relation between obesity and vitamin D status, we did not discern any significant differences in plasma 25(OH)D concentrations when comparing the 2 groups matched for insulin sensitivity but differing in BMI and WC (NW-IS group compared with the OB-IS group: 32 ± 9 compared with 30 ± 10 ng/mL). However, data in Table 2 show that a greater proportion of individuals in the 2 OB groups had 25(OH)D concentrations ≤30 ng/mL as compared with the NW group (54% compared with 35%). Similarly, results in Table 3 show that the tertile of subjects with the lowest 25(OH)D concentrations had somewhat higher BMI and SSPG values than did the other 2 tertiles. Although none of these small differences were significant, it is possible that they would have reached significance if we had studied much larger populations. Thus, our findings do not necessarily conflict with earlier studies that emphasized an association between obesity and low concentrations of circulating 25(OH)D (14–17). However, our study did not find a clear link between obesity, 25(OH)D concentrations, and insulin resistance, and there are substantial numbers of obese individuals with low plasma 25(OH)D concentrations who are insulin sensitive.

With regard to the relation between 25(OH)D concentrations and insulin sensitivity in equally obese individuals, the fundamental question is whether differences in 25(OH)D appear to determine whether an individual is insulin resistant or insulin sensitive. On the basis of the individuals in this study, the answer to this question appears to be “no,” because 25(OH)D concentrations were only 2 ng/mL lower in the OB-IR group (28 ± 6 ng/mL) than in the OB-IS group (30 ± 10 ng/mL). Thus, despite an approximate 3-fold difference in mean SSPG concentration (221 ± 32 compared with 75 ± 14 mg/dL), there was no significant difference in 25(OH)D concentrations between OB-IR and OB-IS individuals. Furthermore, when the OB-IR group was further subdivided into those individuals with a 25(OH)D concentration ≤30 or >30 ng/mL, SSPG concentrations were not different: 217 ± 32 mg/dL and 229 ± 32 mg/dL for 25(OH)D concentrations ≤30 and >30 ng/mL, respectively. Similarly, when the OB-IS group was subdivided by using a 25(OH)D cutoff of 30 ng/mL, SSPG concentrations were low (∼75 mg/dL) in both high- and low-25(OH)D subgroups. Essentially identical findings were seen when a 25(OH)D cutoff of 20 ng/mL was used, but only 17% of the entire study population had values <20 ng/mL—too few in each group for a formal statistical analysis. Consequently, our finding that 3-fold differences in insulin-mediated glucose disposal can exist in equally obese individuals, in the absence of any difference in 25(OH)D concentration, may not apply to populations with large numbers of subjects with 25(OH)D concentrations <20 ng/mL. Our inability to identify an association between low 25(OH)D concentrations and insulin action is of interest in light of the results of Mitri et al (13), which showed that cholecalciferol administration improved insulin secretion, but not insulin sensitivity, in individuals with mean 25(OH)D concentrations ∼24 ng/mL, a value similar to the mean value of 28 ng/mL in the OB-IR group.

In conclusion, 25(OH)D concentrations varied overall by ≥4-fold in our 3 experimental groups of apparently healthy volunteers enrolled in this study. Despite this variability, differences in 25(OH)D did not appear to be associated with wide variations in either the degree of obesity (when matched for measures of insulin action) or insulin sensitivity (when matched for degree of obesity). On the basis of these findings, we would suggest that differences in circulating 25(OH)D concentrations in apparently healthy individuals are not likely to play a major role in the modulation of insulin-mediated glucose disposal. On the other hand, there are several important questions that were not addressed in our study. For example, the results do not provide any insight as to the role, if any, that low 25(OH)D concentrations might have on the pathogenesis of T2D. Furthermore, we did not evaluate the possibility that administration of large doses of vitamin D might enhance insulin sensitivity in insulin-resistant individuals. We also did not address the possibility that differences in circulating plasma 25(OH)D concentrations might modulate pancreatic β cell function and thereby provide a putative link between vitamin D and T2D. Finally, we did not examine vitamin D receptor polymorphisms to determine whether any molecular difference within target cells might contribute to the modulation of insulin action by vitamin D (25).

It is also important to explicitly acknowledge that our study had certain intrinsic drawbacks: it was cross-sectional in nature; it relied on additional analyses of stored, frozen samples obtained from previous studies; and we cannot determine at what season of the year the specimens were obtained. In addition, our experimental population was healthy and fit and lives at a sunny and warm latitude, which would lead to increased time spent outdoors. It is also possible that if our 3 experimental groups of 26 individuals each was increased several-fold, the very small differences in 25(OH)D concentrations could reach significance. On the other hand, there is evidence from previous publications that the impact of differences in degree of adiposity and/or physical fitness can be shown in experimental groups of sizes comparable to the number of individuals enrolled in this study (6, 26). Thus, despite the imperfections of our study, we believe it reasonable to conclude that 1) several-fold differences in circulating vitamin D concentrations are not associated with differences in a specific and quantitative measure of insulin-mediated glucose disposal in a population of apparently healthy individuals, in whom approximately half were either vitamin D deficient or vitamin D insufficient, and 2) differences in degree of obesity may be associated with lower plasma 25(OH)D concentrations, but the presence of insulin resistance in obese individuals was not associated with differences in 25(OH)D concentrations.

Acknowledgments

The authors’ responsibilities were as follows—CAL, DF, and GMR: designed the research; CAL: conducted the research; DA, DF, and GMR: participated in data analysis, statistical evaluation, and manuscript preparation; and GMR: had primary responsibility for final content. All authors read and approved the final manuscript. There were no conflicts of interest to disclose.

Footnotes

4

Abbreviations used: IR, insulin resistant; IS, insulin sensitive; NW, normal weight; OB, obese; SSPG, steady state plasma glucose; SSPI, steady state plasma insulin; T2D, type 2 diabetes; WC, waist circumference; 25(OH)D, 25-hydroxyvitamin D.

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